We have identified two co-inhibitory molecules of the B7 family, B7-H1 and B7-H4, which inhibit T cell responses in an antigen-dependent fashion. The inhibitory effect of B7-H1 is mediated, at least in part, through the PD-1 receptor, and BTLA is also a putative receptor for B7-H4. Preliminary data from our laboratory and others demonstrate that B7-H1 and B7-H4, upon interaction with their counter-receptors on T cells, constitutes essential immunologic checkpoints in the down-regulation of effector T cell responses to antigens. Importantly, both B7-H1 and B7-H4 are broadly expressed on human cancers and are implicated in the suppression of T cell responses in the tumor's micro-environment. The central hypothesis of this proposal is that B7-H1 and B7-H4 are critical components within the tumor micro-environment to counterattack effector T cells through their co-inhibitory receptors. Blockade of these co-inhibitory receptors should protect tumor antigen-specific effector T cells from immune suppression, leading to potentiation of therapeutic tumor immunity. To test this, we will evaluate immune stimulatory effects of antagonist mAb to B7-H1 and B7-H4 in mouse pancreas and ovarian cancer models. Combinatorial approaches to integrate cancer vaccines, co-stimulation, and manipulation of regulatory T cells, will be explored. Furthermore, we will develop and characterize antagonist mAb to human B7-H1 and B7-H4 in xenograft models of human pancreas and ovarian cancers. Finally, new antagonist mAb will also be developed to block the inhibitory receptor PD-1 and BTLA-4 as complementary approaches to maximize therapeutic efficacy. We anticipate that these studies will provide a foundation for immediate translation of these biologies and approaches into new clinical trials of immunotherapy for pancreas and ovarian cancers.